5′ UTR CGG repeat expansion inGIPC1is associated with oculopharyngodistal myopathy

Abstract

Oculopharyngodistal myopathy is a late-onset degenerative muscle disorder characterized by ptosis and weakness of the facial, pharyngeal, and distal limb muscles. A recent report suggested a non-coding trinucleotide repeat expansion in LRP12 to be associated with the disease. Here we report a genetic study in a Chinese cohort of 41 patients with the clinical diagnosis of oculopharyngodistal myopathy (21 cases from seven families and 20 sporadic cases). In a large family with 12 affected individuals, combined haplotype and linkage analysis revealed a maximum two-point logarithm of the odds (LOD) score of 3.3 in chromosomal region chr19p13.11-p13.2 and narrowed the candidate region to an interval of 4.5 Mb. Using a comprehensive strategy combining whole-exome sequencing, long-read sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal CGG repeat expansion in the 5′ UTR of the GIPC1 gene that co-segregated with disease. Overall, the repeat expansion in GIPC1 was identified in 51.9% independent pedigrees (4/7 families and 10/20 sporadic cases), while the repeat expansion in LRP12 was only identified in one sporadic case (3.7%) in our cohort. The number of CGG repeats was <30 in controls but >60 in affected individuals. There was a slight correlation between repeat size and the age at onset. Both repeat expansion and retraction were observed during transmission but somatic instability was not evident. These results further support that non-coding CGG repeat expansion plays an essential role in the pathogenesis of oculopharyngodistal myopathy.

Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases

“…Thus, like neurodegenerative polyQ diseases, which are caused by CAG repeat expansions embedded in diverse ORFs that are translated into toxic polyglutamine-containing proteins, we propose that NIID and FXTAS represent a novel class of disorders, polyG diseases, where expansions of GGC repeats embedded in diverse upstream ORFs are translated into toxic polyG-containing proteins ( Figure S6 ). Of interest, GGC repeat expansions located in the 5′ UTRs of the LRP12 , GIPC1 , and NUTM2E (also known as FAM22E) genes have been recently identified as the cause of the OPDM and OPML neuromuscular and neurodegenerative disorders ( Ishiura et al., 2019 ; Deng et al., 2020 ; Xi et al., 2021 ). OPDM and OPML share some overlapping symptoms and similar histopathological features with NIID and FXTAS.…”

“…Third, expanded repeats can be translated by canonical initiation to AUG or near-cognate start codons or by translation initiation directly within the repeat through a novel mechanism called repeat-associated non-AUG (RAN) translation (Zu et al, 2011), into proteins containing a pathogenic stretch of repeated amino acids. Progress in long-read and whole-genome sequencing has recently unveiled a dozen novel microsatellite expansions located in the ''non-coding'' part of the human genome as pathogenic causes, notably an intronic AGrich repeat expansion in the RFC1 gene in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) (Cortese et al, 2019;Rafehi et al, 2019); 6 similar intronic AT-rich repeat expansions in benign adult familial myoclonic epilepsy (BAFME) 1-6 and 5 similar 5 0 UTRembedded GC-rich repeat expansions in fragile X-associated tremor/ataxia syndrome (FXTAS), neuronal intranuclear inclusion disease (NIID), oculopharyngodistal myopathy (OPDM), and oculopharyngeal myopathy with leukoencephalopathy (OPML), neuromuscular and neurodegenerative syndromes with some overlapping symptoms and similar histopathological features (Hagerman et al, 2001;Ishiura et al, 2019;Sone et al, 2019;Deng et al, 2019Deng et al, , 2020Tian et al, 2019;Xi et al, 2021; review in Ishiura and Tsuji, 2020). Among these later disorders, NIID, also known as neuronal intranuclear hyaline inclusion disease (NIHID) and intranuclear inclusion body disease (INIBD), is a rare genetic disease characterized by the presence of intranuclear inclusions in the central and peripheral nervous systems and in multiple other organs (Lindenberg et al, 1968;Munoz-Garcia and Ludwin, 1986;Sone et al, 2016).…”

Deciphering Neurodegenerative Diseases Using Long-Read Sequencing

“…GIPC1 with repeat expansions accounted for 50% and 51.9% of Chinese patients with OPDM in these 2 studies, respectively, whereas only 3.6% of the Japanese population. 24 , 25 This demonstrates that noncoding trinucleotide repeat expansions in GIPC1 may be the most frequent cause of the Chinese OPDM cohort.…”

“…Intriguingly, an independent strategy but also involving LRS in Chinese OPDM cases identified similar results with a slight difference in the repeat motif, that is, CGG. 25 There is the possibility that the same repeat expansions are described in different manners, such as based on various kinds of DNA reference sequences of GIPC1 . GIPC1 with repeat expansions accounted for 50% and 51.9% of Chinese patients with OPDM in these 2 studies, respectively, whereas only 3.6% of the Japanese population.…”

Precise Characterization of Bombyx mori Fibroin Heavy Chain Gene Using Cpf1-Based Enrichment and Oxford Nanopore Technologies

“…In fact, these “junk” DNAs are not useless, and they play a very important role in nucleus formation, chromatin rearrangement, tumorigenesis, and gene expression regulation [ 3 , 4 , 5 , 6 , 7 ]. Tandem repeats are mainly located in non-coding regions, such as in the telomeric and centromeric DNA [ 8 , 9 , 10 ], and a few are located in protein-coding genes, such as those encoding spider silk spidroin [ 11 , 12 ], B. mori silk fibroin [ 13 , 14 , 15 ], disease-related genes [ 8 , 16 , 17 ]. Variation in the number of repeat units in protein-coding genes determines gene polymorphism and affects the function of the gene.…”